Therapeutic envelope vaccination in combination with antiretroviral therapy temporarily rescues SIV‐specific CD4+ T‐cell‐dependent natural killer cell effector responses in chronically infected rhesus macaques

Natural killer (NK) cells are essential components of the immune system, and due to their rapid response potential, can have a great impact during early anti‐viral immune responses. We have previously shown that interleukin‐2‐dependent NK and CD4⁺ T‐cell co‐operative immune responses exist in long‐term simian immunodeficiency virus (SIV) ‐infected controlling macaques and can be rescued in SIV‐infected non‐controlling macaques by a short course of antiretroviral therapy (ART). Given that co‐operative responses may play an important role in disease prevention and therapeutic treatment, in the present study we sought to determine if these responses can be enhanced in chronically SIV‐infected macaques by vaccination with a single‐dose of envelope protein given during ART. To this end, we treated 14 chronically SIV‐infected macaques with ART for 11 weeks and gave 10 of these macaques a single intramuscular dose of SIV gp120 at week 9 of treatment. ART significantly decreased plasma and mucosal viral loads, increased the numbers of circulating CD4⁺ T cells in all macaques, and increased T‐cell‐dependent envelope‐ and gag‐specific interferon‐γ and tumour necrosis factor‐α production by circulatory CD56⁺ NK cells. The therapeutic envelope immunization resulted in higher envelope‐specific responses compared with those in macaques that received ART only. Functional T‐cell responses restored by ART and therapeutic Env immunization were correlated with transiently reduced plasma viraemia levels following ART release. Collectively our results indicate that SIV‐specific T‐cell‐dependent NK cell responses can be efficiently rescued by ART in chronically SIV‐infected macaques and that therapeutic immunization may be beneficial in previously vaccinated individuals.